6ud2 | pdb_00006ud2
co-crystal structure of compound 1 bound to human Mcl-1
Structural highlights
Function[MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1] Publication Abstract from PubMedOverexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an alpha-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model. Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an alpha-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.,Rescourio G, Gonzalez AZ, Jabri S, Belmontes B, Moody G, Whittington D, Huang X, Caenepeel S, Cardozo M, Cheng AC, Chow D, Dou H, Jones A, Kelly RC, Li Y, Lizarzaburu M, Lo MC, Mallari R, Meleza C, Rew Y, Simonovich S, Sun D, Turcotte S, Yan X, Wong SG, Yanez E, Zancanella M, Houze J, Medina JC, Hughes PE, Brown SP J Med Chem. 2019 Nov 27;62(22):10258-10271. doi: 10.1021/acs.jmedchem.9b01310., Epub 2019 Nov 18. PMID:31736296[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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